He was born in Atlanta and currently lives in the nearby suburb of Marietta. Shortly after graduating from the University of Georgia, he opened the first Cobb County office of Northside Realty, a prominent Atlanta-area real estate firm. He became company president in 1979, a post he held for 22 years, during which Northside became the biggest independent real estate company in Georgia.

Isakson first entered Republican politics in 1974, losing a race for the Georgia House of Representatives in an eastern Cobb County district. He ran again in 1976 and won. He served seven terms in the House, the last two as minority leader. He was the Republican candidate for governor of Georgia in 1990, losing to Democratic lieutenant governor Zell Miller. Two years later, he was elected to the Georgia Senate and served two terms.

In 1996 he ran in the Republican primary for the Senate seat being vacated by Sam Nunn. However, when he announced his candidacy, he declared that he was the pro-choice Republican candidate. This was a very risky and unpopular move, as the Georgia Republican Party is strongly pro-life and the Republican primary electorate is tilted far to the right. Derided as being "too liberal," he managed to win the first round, but lost in the runoff to Guy Milner.

In January 1999, 6th District Congressman and House Speaker Newt Gingrich faced a revolt in his caucus after the Republicans lost five seats in the midterm elections two months earlier. He'd predicted a 30-seat Republican gain. Amid the ruckus, Gingrich decided not only to resign as Speaker, but also not to take his seat for an 11th term. Isakson ran for the seat in a special election in February and won easily, largely because he had more name recognition than any other candidate. He finished 40 points ahead of the runner-up. He won the seat in his own right in 2000 and was reelected in 2002. The 6th is arguably the most Republican district in Georgia and one of the most Republican in the South, and Isakson never faced a truly serious or well-financed challenge in either election.

In late 2003, Miller opted not to run for a full term in the Senate (he'd been appointed to fill out the term of the late Republican Senator Paul Coverdell). Isakson immediately entered the race. He quickly picked up the endorsements of much of the Republican establishment, including notably George W. Bush. However, a large number of Republicans in Georgia had never forgiven him for his pro-choice stance in 1996, despite his rightward turn on social issues (see below). Georgia Right to Life endorsed both of Isakson's opponents, 8th District Congressman Mac Collins and businessman Herman Cain. Even without the furor over Isakson's stance on abortion, the race was widely expected to be one of the closest in the primary cycle. However, to the surprise of most experts, Isakson easily won the nomination in the first round with 53 percent of the vote, with Cain in a distant second. In the general election, he trounced the Democratic candidate, 4th District Congresswoman Denise Majette, by 16 points. Isakson's election marked the first time in Georgia's history that both Senate seats had been held by Republicans (Saxby Chambliss had won the other seat by defeating Nunn's successor, Max Cleland, two years earlier).

Since 1996, Isakson has drifted considerably to the right on social issues. He is now anti-abortion (with some exceptions), anti-gay marriage and pro-gun rights. On the Issues, a nonpartisan Web site that rates candidates, labels Isakson "a Libertarian-leaning conservative."

When he ran for the 6th in 1999, he largely ignored the issue; however, in 2003-2004, in his campaign for the Senate, he took the same position as President Bush, saying we needed to "create a culture of life" in America. At the same time, he insisted that throughout his career he had never changed his position on the issue.

Isakson is often referred to as a RINO by those who opposed his nomination in 1996 and 2004. In fact, pundits such as Fred Barnes have said his predecessor, Zell Miller was more conservative despite being a Democrat. Despite the claims by some that Isakson is not conservative enough, some conservative organizations counter this claim. Isakson has been given an "A" rating by the National Rifle Association, the "Hero of the Taxpayer" award by Citizens Against Government Waste, and a "92" rating on a scale of 100 by the Christian Coalition of America (incidentally, the same score Mac Collins received). He also received a perfect 100 rating from the American Conservative Union. In the Senate Isakson is currently working to oppose the Castle/Degette Stem Cell Bill by offering an alternative that does not allow for the destruction of a human embryo. Isakson is well-respected among Democrats and Republicans, and is considered to be a political heir of sorts to Nunn and Coverdell.

Isakson is a member of the Republican Main Street Partnership.